Glomerulosclerosis (GS) is a pathological process characterized by expansion of the glomerulus secondary to increased accumulation of mesangial matrix and scarring/fibrosis of the tubulointerstitium; processes that may lead to proteinuria and renal failure. Once set in motion, processes underlying GS are usually irreversible; thus, identification of early pathogenic events is a key step in their prevention/treatment. Key roles for glomerular epithelial cells, or podocytes, in the pathogenesis of glomerular diseases are speculated, as early events in GS include progressive podocyte damage, and finally, irreversible loss. Receptor for AGE RAGE) is expressed at low levels in the normal human/mouse kidney in homeostasis, where glomerular expression is limited largely to the podocyte, and in disease settings, RAGE is expressed in infiltrating inflammatory cells such as mononuclear phagocytes (MPs), and, in addition, expression of RAGE is enhanced in the podocyte, beyond that observed at baseline. In human and murine (db/db) diabetes, and subsequent to adriamycin (ADR) exposure in BALB/c mice, expression of podocyte RAGE is increased, in parallel with increased expression of RAGE ligands, Advanced Glycation Endproducts; and proinflammatory S100/calgranulins, especially in infiltrating MP. Administration of soluble (s) RAGE to BALB/c mice exposed to ADR suppressed enlargement of the kidney; glomerular and mesangial expansion; and thickening 3f the GBM, in parallel with decreased albuminuria. We hypothesize that activation of podocyte and/or MP RAGE triggers cellular perturbation in the ADR-treated kidney, leading to enhanced permeability and inflammation early after injury; events that augur the development of oxidant stress, generation of cytokines and growth factors linked to fibrosis at later stages after ADR. We will dissect the effects of RAGE in the development/progression of GS in a murine model of ADR-induced nephropathy employing RAGE null (0) mice and transgenic mice expressing inactivated RAGE in podocytes or cells of MP lineage. We propose that identification of RAGE-dependent mechanisms in glomerular diseases may lead to novel therapies to prevent, stabilize or reverse the course of chronic GS.